AORTIC STENOSIS – ETIOLOGY, PATHOPHYSIOLOGY AND TREATMENT potx

Contents Preface IX Part 1 Introduction 1 Chapter 1 Aortic Stenosis - New Insights in Stenosis Progression and in Prevention 3 Parolari Alessandro, Trezzi Matteo, Merati Elisa, Filipp

– ETIOLOGY, PATHOPHYSIOLOGY AND TREATMENT Edited by Masanori Hirota

Aortic Stenosis – Etiology, Pathophysiology and Treatment

Edited by Masanori Hirota

Published by InTech

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Contents

Preface IX Part 1 Introduction 1

Chapter 1 Aortic Stenosis - New Insights in

Stenosis Progression and in Prevention 3

Parolari Alessandro, Trezzi Matteo, Merati Elisa, Filippini Sara and Alamanni Francesco

Part 2 Etiology and Pathophysiology 23

Chapter 2 Aortic Stenosis: Geriatric Considerations 25

Petar Risteski, Andreas Zierer, Nestoras Papadopoulos, Sven Martens, Anton Moritz and Mirko Doss

Chapter 3 Pathophysiologic Mechanisms of

Age – Related Aortic Valve Calcification 33

Alexandros Alexopoulos, Nikolaos Michelakakisand Helen Papadaki

Part 3 Diagnosis and Prognosis 49

Chapter 4 Asymptomatic Aortic Stenosis

- Prognosis, Risk Stratification and Follow-Up 51

Paoli Ursula and Dichtl Wolfgang Chapter 5 Stress Testing in Patients

with Asymptomatic Severe Aortic Stenosis 67

Asim M Rafique, Kirsten Tolstrup and Robert J Siegel Chapter 6 Analog Simulation of Aortic Stenosis 75

M Sever, S Ribarič, F Runovc and M Kordaš

Part 4 Surgical and Interventional Treatments 89

Chapter 7 Minimally Invasive Aortic Valve Surgery -

New Solutions to Old Problems 91

Juan Bustamante, Sergio Cánovas and Ángel L Fernández

Aortic Stenosis and Calcified Ascending Aorta During Aortic Valve Replacement 115

Masanori Hirota, Joji Hoshino, Yasuhisa Fukada, Shintaro Katahira, Taichi Kondo, Kenichi Muramatsu and Tadashi Isomura

Chapter 9 Transcatheter Aortic Valve Implantation:

New Hope for Inoperable and High-Risk Patients 131

Kentaro Hayashida and Thierry Lefèvre Chapter 10 Management of Congenital Aortic

Stenosis by Catheter Techniques 153

Mehnaz Atiq

Part 5 Molecular Considerations in Aortic Stenosis 165

Chapter 11 Proteomics - A Powerful Tool to Deepen the

Molecular Mechanisms of Aortic Stenosis Disease 167

Felix Gil-Dones, Fernando de la Cuesta, Gloria Alvarez-Llamas, Luis R Padial, Luis F López-Almodovar, Tatiana Martín-Rojas, Fernando Vivanco and Maria G Barderas

Chapter 12 The Inflammatory Infiltrate in Calcific Aortic Stenosis

is Characterized by Clonal Expansions of T Cells and is Associated with Elevated Proportions of Circulating Activated and Effector Memory CD8 T Cells 187

Robert Winchester and Susheel Kodali Chapter 13 Natriuretic Peptides in Severe

Aortic Stenosis - Role in Predicting Outcomes and Assessment for Early Aortic Valve Replacement 203

Aaron Lin and Ralph Stewart Chapter 14 Cellular and Neuronal Aspects in Aortic Stenosis 221

J Kerand WFP Van Heerden

Part 6 Associated Disorders with Aortic Stenosis 229

Chapter 15 Severe Calcific Aortic Valve Stenosis

and Bleeding: Heyde's Syndrome 231

Giampaolo Zoffoli, Domenico Mangino, Andrea Venturini, Angiolino Asta, Alberto Terrini, Chiara Zanchettin, Francesco Battaglia and Elvio Polesel

Chapter 16 Hybrid Procedure in Neonatal Critical

Aortic Stenosis and Borderline Left Heart:

Buying Time for Left Heart Growth 239

Ward Y Vanagt, Stephen C Brown and Marc Gewillig

Preface

At the moment, aortic stenosis (AS) is the most prevalent valvular disease in the developed countries Pathological and molecular mechanisms of AS have been investigated in many aspects, and new therapeutic devices, such as trans-catheter aortic valve implantation, have been developed as a less invasive treatment for high-risk patients Due to advanced prevalent age of AS, further research results and technology are required to treat elderly patients for longer life expectancy

This book is an effort to present an up-to-date account of existing knowledge, involving recent development in this field There are 15 chapters written by several expert researchers and clinicians, including cardiologists, cardiac surgeons, pediatricians, physiologists, pathologists and immunologists These opinion leaders described details of established knowledge, as well as newly recognized advances associated with diagnosis, treatment and mechanism in their speciality This book will enable close intercommunication to another field and collaboration technology for new devices We hope that it will be an important source, not only to clinicians, but also to general practitioners, contributing to development of better therapeutic adjuncts in the future

Masanori Hirota, MD, PhD

Department of Cardiovascular Surgery, Hayama Heart Center, Kanagawa,

Japan

Introduction

Aortic Stenosis - New Insights in Stenosis Progression and in Prevention

Parolari Alessandro, Trezzi Matteo, Merati Elisa,

Filippini Sara and Alamanni Francesco

Dept Of Cardiovascular Sciences, University of Milano,

Centro Cardiologico Monzino IRCCS, Milano

1.2 Etiology

AS is the obstruction of blood flow across the aortic valve AS has several etiologies including rheumatic fever, congenital unicuspid or bicuspid valve, and degenerative calcific changes of the valve Rheumatic heart disease is the main cause of valvular heart disease worldwide, but fewer than 10% of AS cases in the United States and Western Europe are rheumatic In contrast, senile, calcific disease of the aortic valve and bicuspid valve disease are responsible for the vast majority of AS cases in those countries Since the incidence of AS increases with age and the Western population as a whole is aging, increased numbers of patients presenting with AS are expected in the near future Currently, the incidence of AS is estimated to be 1−2% among those over 65 years of age and 4% among octagenarians Rheumatic AS is rarely an isolated disease andusually occurs in conjunction with mitral valve stenosis Rheumatic AS is characterized by diffuse fibrous leaflet thickeningof the tricuspid valve with fusion of the commissures with scarring and eventual calcification of the cusps A congenital malformation of the valve may also result in stenosis and is the most common cause in young adults Bicuspid aortic valve is the most common cause of aortic stenosis in patients under age 65 About 2% of people are born with aortic valves that have only two cusps (bicuspid valves) Although bicuspid valves usually do not impede blood flow when the patients are young, they do not open as widely as normal valves with three cusps Therefore, blood flow across the bicuspid valves is more turbulent, causing increased wear and tear on the valve leaflets Over time, excessive wear and tear leads to calcification,

scarring, and reduced mobility of the valve leaflets About 10% of bicuspid valves become significantly narrowed, resulting in the symptoms and heart problems of aortic stenosis The most common cause for AS in adults is senile degenerative AS, with the calcification

of a normal trileaflet or a congenital bicuspid valve (4) Even if it was considered to be the resultof years of mechanical stress on an otherwise normal valve,the evolving concept is that the degenerative process leadsto proliferative and inflammatory changes Calcific aortic-valve disease refers to progressive aortic leaflet thickening and calcification, beginning with the early lesion of aortic-valve sclerosis leading to advanced leaflet disease of aortic-valve stenosis, characterized by restricted leaflet motion and outflow obstruction The pathobiology of the aortic-valve lesion involves an atheromatous, osteogenic, inflammatory process sharing some histologic similarities with coronary atherosclerosis (5)

1.3 Pathophysiology

Valvular aortic stenosis results in chronic left ventricular pressure overloading At any stage

of life, however, the natural history of aortic stenosis largely reflects the functional integrity

of the mitral valve As long as adequate mitral valve function is maintained, the pulmonary bed is protected from the systolic pressure overloading imposed by aortic stenosis Compensatory concentric left ventricular hypertrophy allows the pressure-overloaded ventricle to maintain stroke volume with modest increases in diastolic pressure, and patients remain asymptomatic for many years In early stages the development of concentric hypertrophy appears to be an appropriate and beneficial adaptation to compensate for high intracavitary pressures Unfortunately, this adaptation often carries adverse consequences The hypertrophied heart may have reduced coronary blood flow and also exhibit a limited coronary vasodilator reserve, even in the absence of epicardial coronary artery disease, that`s why one of the symptoms is angina In later stages of severe AS, cardiac output declines, and the pulmonary artery pressure rises,leading to pulmonary hypertension The first symptom of this condition is increasing shortness of breath and the last consequence is heart failure The onset of any of the classic symptoms of left ventricular outflow obstruction—angina, syncope, or heart failure—in a patient with valvular aortic stenosis indicates advanced valve disease and should be carefully and promptly evaluated Syncope most commonly is due to the reduced cerebral perfusion that occurs during exertion secondary to the decrease in arterialpressure consequent to peripheral vasodilation in the presenceof a fixed cardiac output For years the cause of the calcification of the aortic valve was thought to be the passive accumulation of calcium in the valve leaflets, causing nodular deposits and an eventual stenosis Clinical studies have demonstrated that the risk factors for this process include hypercholesterolemia, diabetes, smoking, hypertension, male sex, and elevated high sensitivity C-reactive protein (6), suggesting that calcification of the aortic valve results from an inflammatory process triggered by these factors of atherosclerotic risk and that drug therapies to retard this process may be a useful strategy in the future Hyperuricemia has been identified as another risk factor for development of aortic valvular disease Calcific AS is also observed in a number of other conditions,including Paget disease

of bone and end-stage renal disease.Ochronosis with alkaptonuria is another rare cause of

AS, which also can cause a rare greenish discoloration of the aortic valve Recent experimental models have shown that there is a relationship between hypercholesterolemia and the development of aortic valvular disease (7) Studies of human tissue also suggest

that the development of aortic valvular calcification represents an active cellular biology O’Brien et al have described the early valvular lesion (aortic sclerosis) as an entity very similar to the early lesion of the atherosclerotic plaque (8) These lesions show similarities to the atherosclerotic process, with a predominance of ‘atherogenic’ lipoproteins, especially LDL and lipoprotein(a), evidence of LDL oxidation, inflammatory cellular infiltrates and the development of calcification The presence of lipids stimulates the production of many factors such as modified TGF-b1, tumor necrosis factor and cytokines in the aortic valve leaflets (9) In particular early valvular sclerotic lesions demonstrate a chronic inflammatory cell infiltrate (macrophages and T lymphocytes), lipid accumulation (apolipoprotein [apo] B, apo(A) and apo(E) and α-actin–expressing cells in the lesion and adjacent fibrosa; end-stage calcified valves contain mature lamellar bone with expression of specific bon markers important in the development of osteoblast bone formation (10) In addition, angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1) and type 2 (AT2) receptors are present in stenotic aortic valves, implicating this signaling pathway in the disease process (11) These observations are analogous to the cellular findings in vascular atherosclerosis and corroborate epidemiological studies that showed similar associations of clinical risk factors with both atherosclerosis and aortic valve disease (12) The mechanism for valvular calcification is similar to skeletal bone formation and that calcification occurs in areas of neoangiogenesis, which is stimulated by an active inflammatory process and the release of vascular endothelial growth factor (VEGF) VEGF is well known to play a key role in angiogenesis in pathological inflammatory diseases.(13) Deckers et al (14) have suggested that VEGF regulates bone remodeling by attracting endothelial cells and by stimulating osteoblast differentiation Our findings indicate that VEGF is localized to cells in inflammatory regions of the valve fibrosa, specifically the macrophages and myofibroblasts Rajamannan recently demonstrated that an osteoblast phenotype is associated with nonrheumatic, degenerative calcific aortic stenosis The current data, including the production of osteopontin and osteocalcin proteins (both osteoblast cell products) and proliferating myofibroblast cells synthesizing bone matrix proteins, indicate that a similar osteoblast-like process that occurs in degenerative calcific aortic stenosis develops in the calcification process in rheumatic valves (10) Although calcification in rheumatic valves has been described in the literature for years, the cellular mechanisms responsible for the calcification have not been previously described These new observations support the hypothesis that mineralization of rheumatic cardiac valve tissue is similar to skeletal bone formation that is associated with neoangiogenesis and show that studying this disease process will provide important information on the treatment of valvular heart disease (15)

In contrast to mitral valve degeneration, Caira et al found that the Lrp5/Wnt3 signaling markers are present in the calcified aortic valve greater than the degenerative mitral valve These data provide the evidence of a mechanistic pathway for the initiation of bone differentiation in degenerative valve lesions, which is expressed in the mitral valve as a cartilage phenotype and in the calcified aortic valve as a bone phenotype These results indicate that there is a continuum of an earlier stage of osteoblast bone differentiation in the mitral valves as compared with the calcified aortic valves In normal adult skeleton formation, the initiation of bone formation occurs with the development of a cartilaginous template, which eventually mineralizes and forms calcified bone Therefore, the mitral valve expresses an early cartilage formation, and the aortic valve demonstrates the mineralized osteoblast phenotype,which follows the spectrum of normal skeletal bone formation The

calcified aortic valves express an osteoblast phenotype: “bone” in the aortic valve that is responsible for the stenosis present in symptomatic aortic stenosis requiring surgical valve replacement This study demonstrates that hypercholesterolemia may play a role in the initiating event of calcification This is the first study to demonstrate the presence of chondrocytes in mitral valves, and osteoblasts in aortic valves implicating this pathologic mechanism in the development of mitral regurgitation in myxomatous mitral valves and stenosis in calcific aortic valves (16) In bicuspid aortic valve, the calcification and progressive stenosis typically occur faster than in tricuspid aortic valves, Rajamannan demonstred that the eNOS protein expression was decreased in the BAV vs the tricuspid aortic valves This data provides further evidence of the potential functional importance of eNOS enzymatic activity in the developmental level for the formation of the congenital heart abnormality in addition to the actual role in the calcification process More, bone sialoprotein, osteocalcin, and osteopontin are increased and are markers of extracellular matrix synthesis in the valve whereas Notch1 is decreased in the valve The protein and RNA expression also demonstrated a decrease in overall Notch1 in these disease tissues, indicating that the loss of normal Notch1 is necessary for valve calcification similar to the implications of the loss of function mutation in the genetic study Overall, the loss of Notch1 function and the increase in Lrp5 signaling demonstrate the role of these important regulators of bone metabolism in these diseased tissues Than, the mechanism of BAVD results in a decrease in Notch1 function and an increase in Lrp5 expression which activates bone formation within the valve myofibroblast (17).

2 Clinical presentation

The diagnosis of the aortic stenosis is usually made on physical examination with detection

of the classical systolic outflow murmur The severity of aortic stenosis can be determined reliably by echocardiography, based on the extent of the valvular calcification, the peak flow velocity across the valve, the mean gradient and the valvular area computed by the continuity equation Evaluation of serial echocardiograms in patients with aortic stenosis make it possible to obtain valuable information over a period of time to determine the progression of the disease and the timing of surgery (9)

2.1 Signs and symptoms

The classical symptoms of AS are angina, dispnea, syncope, and heart failure, which represent also the dramatic inflection in the natural history of this disease

In adults with AS, the obstruction develops gradually Many patients with aortic stenosis will remain asymptomatic for decades The diagnosis of aortic stenosis is usually made in the asymptomatic patient on the basis of a systolic murmur on auscultation and confirmed

by echocardiography The development of symptoms therefore is a critical point in the natural history of patients with AS, infact the risk of sudden death in asymptomatic patient with initial manifestation of severe aortic stenosis is very low (<1% per year ), but it is high once any symptom is present, so that valve surgery is appropriate with even mild symptoms

Most prospectively followed patients present with more subtle symptoms, typically decreased exercise tolerance, or dyspnea on exertion It is not uncommon for patients to decrease their activity level below their symptom threshold—a careful history comparing

current and last year’s activity levels is needed to recognize that these patients, in fact, are symptomatic

In asymptomatic patients, the risks of valve surgery are weighed against the risk of an adverse outcome without surgical intervention Aortic valve repair is not an option, so that the long-term durability and risks of a prosthetic valve also must be considered (18)

The electrocardiogram demonstrated findings consistent with the presence of left ventricular hypertrophy and show an overload pattern

The chest radiograph has a normal appearance in the vast majority of patients Left ventricular hypertrophy may be present and is demonstrated in the rounding of the left ventricular free wall Severe calcification of the aortic valve can frequently be seen in adult patients with severe or critical aortic stenosis

Echocardiography is the most commonly used noninvasive diagnostic method for assessing the significance of aortic stenosis Two-dimensional echocardiography can determine valvular motion and the presence or absence of valve thickening and calcification However, Doppler echocardiography is necessary to assess the hemodynamic severity of the stenosis Echocardiography is the clinical standard for evaluation of adults with suspected or known valvular AS Anatomic images show the etiology of AS, level of obstruction, valve calcification, leaflet motion, and aortic root anatomy (19)

It is important to determine the severity of aortic stenosis based upon hemodynamic measurements The echocardiographic criteria were established to define the grading of stenosis by ACC/AHA 2006 (20) and includes the following:

Valve area

1 mild aortic stenosis: area > 1.5 cm2

2 moderate aortic stenosis: area 1 to 1.5 cm2

3 severe aortic stenosis: area < 1.0 cm2

Aortic velocity allows classification of stenosis as

1 mild (less than 3.0 m/s)

2 moderate (3 to 4 m/s)

3 severe (>4 m/s)

but in the revision and the update of ACC/AHA guidelines (2006) the grading of aortic stenosis in evaluated also by the transvalvular gradiente as following

1 mild (mean gradient less than 25 mm Hg)

2 moderate (mean gradient 25 to 40 mm Hg)

3 severe (mean gradient greater than 40 mm Hg)

When stenosis is severe and ejection fraction (EF) is normal, the mean transvalvular pressure gradient is normally greater than 40 mm Hg However, when cardiac output is low, severe stenosis can be present with a lower transvalvular gradient and velocity So to grade the severity of the stenosis also the Ef must to be evaluated Doppler echocardiography is also used to determine diastolic dysfunction by the presence of

abnormal left ventricular relaxation. Moderateto severe diastolic dysfunction does not increase early mortalitybut may increase late mortality after AVR Stress echocardiography

is used in patientswith normal left ventricular function (LVF) to demonstrate thepresence of diastolic dysfunction (i.e., signs of elevated leftventricular filling pressure) as the cause of symptom developmentduring exercise

Doppler echocardiography has replaced cardiac catheterization in most centers for evaluation of the hemodynamic severity of aortic stenosis (21) Cardiac catheterization is reserved for hemodynamic evaluation in patients in whom reliable echocardiographic data cannot be obtained or when the clinical and echocardiographic data are divergent Catheterization is also necessary in most patients undergoing aortic valve replacement (usually men with age > 40, post menopausal women, history of coronary artery disease and suspected myocardial ischemia or LV systolic dysfunction) to determine if there is associated coronary artery disease that can be treated at the time of operation (9)

3 Predictors of Aortic Stenosis

3.1 C reactive protein

The dynamic and inflammatory nature of calcific aortic stenosis has been well appreciated

in recent years, and many pathobiologic features of calcific aortic valve disease exhibit striking similarity to coronary atherosclerosis C-reactive protein (CRP), which has been an useful predictive biomarker of the inflammatory process and prognosis of atherosclerosis, is increased in subsets of patients with calcific aortic stenosis, and this has led to the hope that CRP could be used as well to identify those patients likely to progress or develop severe calcific aortic stenosis (22)

Recent data suggest that oxidative stress and high-sensitivity CRP plasma levels as a marker

of systemic inflammation could be involved in the pathogenesis of rheumatic valve disease Therefore, the role of inflammation in rheumatic valve disease progression should be considered Indeed, the persistence of high levels of high-sensitivity CRP has been shown in patients with chronic rheumatic valve disease, particularly in patients with multivalvular disease, who showed significantly higher plasma levels of CRP (23)

If inflammation is the fundamental process of early aortic valve disease, with calcification predominating in the later stages, one might anticipate that markers of inflammation, such

as CRP, would reflect early aortic valve disease activity and perhaps be less useful as a marker in later stages The available data do not support such a concept CRP has been localized in the valve tissue of aortic stenosis in both native valves and bioprosthetic aortic valves, with a positive correlation between serum CRP values and valve CRP expression (24) C-reactive protein values are increased in patients with severe symptomatic aortic stenosis awaiting valve surgery compared with matched controls and decline after aortic valve replacement On the other hand, Navaro et al show that there is no relationship between elevated CRP levels and the presence of calcific aortic-valve disease or of incident aortic stenosis C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease They observed that older age, male gender, hypertension, coronary artery disease, and renal insufficiency, but not CRP values, are associated with the presence of increasing calcific aortic valve abnormality and that CRP values are not related to the progression from a normal aortic valve to aortic sclerosis or stenosis, nor progression from aortic sclerosis to aortic stenosis African-American ethnicity was significantly protective

from developing calcific aortic valve disease How do we make sense of these apparent discrepancies that CRP appears not to reflect the early inflammation phase of calcific aortic valve disease but does reflect the later calcific stages of the disease? The first methodologic consideration is that the single CRP value at study entry may have been too distant from the time that calcific aortic stenosis was developing during the follow-up period to reflect the inflammatory change that would later occur It is also possible that the inflammatory process in early calcific aortic valve disease was not substantial enough to lead to an elevated serum value It is also clear from the previously noted associations between CRP and severe aortic stenosis that CRP may be a more active, direct participant in the later stages of the disease progression and not simply a biomarker passively reflecting the early inflammatory stages of disease CRP provides valuable prognostic information concerning adverse cardiovascular events in coronary disease as well, but it does not reflect the presence or severity of subclinical anatomic coronary artery disease (25) The study by Novaro et al does add important new understanding concerning the genetic determinants

of calcific aortic valve disease Genetic characteristics of calcium metabolism may be central

to the development of valvular calcification, and the observation that African Americans are protected from development of calcific aortic valve disease, may be related to a genetic predisposition toward less calcification of vascular and valve tissue and lower incidence of osteoporosis It would be of enormous value to identify a biomarker to predict patients likely to develop aortic sclerosis and those likely to progress to aortic stenosis Only a few studies have examined the relationship between CRP and aortic stenosis Galante et al (6) published the initial study demonstrating elevated CRP levels in association with calcific aortic stenosis In a surgical series, CRP levels were higher in severe aortic stenosis patients compared to patients with pure aortic regurgitation (26) In those who underwent aortic valve replacement for aortic stenosis, CRP levels decreased from before to 6 months after valve replacement Recently, CRP has been localized in valve tissue of both calcific aortic-valve stenosis and degenerative aortic-valve bioprostheses , with a positive correlation between serum CRP levels and valvular CRP expression Thus, from the available human studies, it is apparent that CRP levels are elevated in aortic stenosis patients with severe disease awaiting surgery, do not correlate with stenosis severity, and decrease after valve replacement, supporting the histologic evidence that the aortic valve is a site of active inflammation (5)

3.2 Others predictors

Whereas cardiovascular risk factors and CRP levels failed to predict incident aortic stenosis, only 4 demographic variables (increasing age, male gender, white ethnicity, and shorter height) were associated with an increased risk of incident aortic stenosis Increasing age is a well-recognized risk factor related to aortic stenosis Gender appears to have an impact on the risk of both aortic stenosis and the degree of aortic valve calcification , with men showing a greater predilection of both (5)

Genetic factors can also be important in the development of valvular calcification In a recent case–control study, 100 patients with similar demographic characteristics were compared, with and without aortic stenosis, and significant differences between the two groups were observed in the genotype of the vitamin D receptors (27) Another study identified polymorphisms of the apolipoproteins AI, B and E as predisposing factors for development

of calcification and valvular stenosis (28) Finally, a unique study by Garg et al

demonstrated the unique signaling pathway Notch as important in the development of calcific aortic stenosis and also congenital heart abnormalities These important studies indicate that genetic predisposition and risk factors may play a role in the development of disease (9) In a recent study Kamalesh et al revealed that diabetes accelerate progression of calcification in subjects who have moderately severe aortic stenosis Therefore, for this patients may need intensive follow-up for their aortic stenosis rather than non diabetic subjects (29) The finding that the multifunctional glycophosphoprotein osteopontin (OPN)

is involved in both cell-mediated inflammation and biomineralization has generated considerable interest in the role of OPN in ectopic calcification and calcific aortic valve disease as shown by Yu et al (30) Although other serum markers, such as C-reactive protein and B-type natriuretic peptide have previously been shown to be associated with aortic calcification and stenosis, OPN is the only molecule that is implicated in both inflammation and biomineralization processes, which lead to aortic valve calcification and subsequent stenosis Also Ferrari and Grau demonstrates a direct correlation of NT-pro-BNP, BNP, and osteopontin and the presence of calcific AS, while fetuin A showed an inverse correlation Plasma ADMA and homocysteine levels were comparable in the calcific

AS patients and healthy individuals A new study analyzed osteopontin level and its phosphorilation status in CAVD and demostred that phospho-threonina levels of purified OPN are higher in healthy controls when compared to CAVD patients This study showed that phospho-OPN prevent calcium deposition, whereas the dephosphorylated protein mimicking the patient’s plasma OPN, lose its protective role allowing calcium depositation

on the cellular surface This data suggest the role of circulating OPN and its phosphorilation status as biomarker and inhibitory factor for the pathogenesis of calcific CAVD (31)

However, recent epidemiologic studies evaluating the independent risk factors for calcific aortic stenosis have demonstrated that the risk factors for aortic stenosis are similar to those

of coronary artery disease, which include hypertension, elevated low-density lipoprotein, smoking, diabetes, and male gender (32) These atherosclerotic risk factors provide the evidence for the potential of medical therapy for this disease process (19)

static muscular demands There are no proven medical treatments to slow or prevent disease progression However, aggressive lipid lowering therapy may be of benefit, especially in patients with less-severe valve calcification, and will ameliorate progression of vascular atherosclerosis that frequently coexists and increases their comorbidity Patients with symptoms and severe aortic stenosis should be considered for operation with aortic valve replacement Delays to surgery have been associated with poorer outcome following operation Over the past two decades, the risk of operation has decreased substantially Isolated aortic valve replacement in a patient less than 70 years old should be able to be performed with a risk of less than 1% The risk should be less than 2–3% among septuagenarians and even less than 5% in octogenarians in the absence of significant comorbidities Therefore, age is not a contraindication to surgery Concomitant coronary artery bypass grafting should be performed for coronary atherosclerosis when epicardial

lesions are >50%

Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, different studies hypothesized that people with elevated high-sensitivity C-reactive protein levels might benefit from statin treatment (33) The treatment of the asymptomatic patient with severe aortic stenosis is more controversial When there is left ventricular dysfunction, valve replacement is indicated even in asymptomatic patients In these patients, the critical increase in afterload has started to overwhelm the compensatory mechanisms of left ventricular hypertrophy and the outcome is poor without surgical intervention Importantly, aortic valve replacement can also now be done with a low operative mortality and there is enhanced durability of the new prostheses Thus, surgery is reasonable to consider in asymptomatic patients when there is critical aortic stenosis and the expected

operative mortality is <1.0% Aortic valve replacement may also be considered for adults

with severe asymptomatic aortic stenosis if there is evidence or high likelihood of rapid progression or when there may be delayed rapid access to medical care if symptoms arose Progression of aortic stenosis may be considered rapid when the Doppler peak velocity

increases by >0.3 m/s per year or when the valve area decreases by >0.1 cm2 per year

4.2 Future directions in medical treatment

As greater understanding of the cellular mechanisms, pathogenesis and progression of aortic valvular disease evolves, new pharmacological strategies are being proposed that are targeted more directly to mechanisms of the disease, both for preventing its progression and ultimately for achieving its regression The two pharmacological agents that have been studied experimentally and that demonstrate the most potential benefit are the HMG-CoA reductase inhibitors (statins) and the ACE inhibitors (19,20,22,33) The clinical implementation of these pharmacological treatments will require a strict validation of the experimental and retrospective studies to date (34–38), in order to establish a clear cause–effect benefit in any pharmacological treatment system

Conventionally ACE-Is are contraindicated in patients with severe AS However, we may safely administer ACE-Is to patients with mild AS because hemodynamic effects of stenotic aortic valve are well compensated in such patients The renin-angiotensin system contributes to the inflammatory nature of the aortic valve lesion Angiotensin converting enzyme (ACE), as well as angiotensin II and the angiotensin II type-1 receptor, have been identified in aortic sclerotic lesions , which stimulate monocyte infiltration and macrophage uptake of modified LDL (34) Calcification, the hallmark characteristic of aortic valve stenosis, is also clearly a feature of the active inflammatory process, occurring in valve

regions of lipid disposition, especially oxidized lipids, with additional stimulus provided by macrophage- and T lymphocyte-produced cytokines Early in the disease process, active microscopic areas of calcification are seen co-localizing in areas of lipoprotein accumulation and inflammatory cell infiltration; as the disease progresses, active bone formation is seen ACE inhibitors are thought to interfere with the renin-angiotensin system and exert beneficial actions on vascular tissues beyond their blood pressure–lowering effects

Regarding statins, there are a number of experimental models testing the effects of a cholesterol diet on the aortic valve in mice model Sarphie (39) demonstrated the first histochemical effects of cholesterol on the development of valvular heart disease Studies by Rajamannan and Charest et al have also shown that endothelial nitric oxide enzyme activity plays a role in the early valve lesions Elevated cholesterol decreases the enzyme expression and induces early mineralization in the aortic valve Therefore, these early studies provide the evidence that aortic valve disease has similar initiating mechanism of oxidative stress that is found in vascular atherosclerosis The next critical step toward understanding of aortic valve calcification is to determine the signaling mechanisms involved in the development of this disease (40) The studies from Mohler (41) and Rajamannan (40) have shown that the aortic valve calcifies secondary to a bone phenotype Recent studies from Rajamannan and Shao et al have demonstrated that the mechanism by which calcification develops is activation of the LDL receptor 5 (Lrp5)/Wnt pathway in the vascular and valvular interstitial cells (40) These studies confirm that the presence of bone formation is the phenotypic expression of calcification in the aortic valve (10) Over time, the valve leaflet synthesizes bone matrix, which eventually calcifies and forms bone If the aortic valve has

an actual biology that is initiated by elevated cholesterol, then in the future, medical therapy such as statins or angiotensin-converting enzyme inhibitors may slow the progression of this disease

Also Nagy et al studied the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis and demonstred that the messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased in thickened and calcified tissue compared with normal areas of the same valves Moreover they showed that leukotriene C4 (LTC4) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification This data suggest the up-regulation of the pathway LT and the potentially detrimental LT-induced effects on valvular myofibroblasts as possible role in the development of aortic stenosi and induce to considerate innovative therapeutic interventions(42)

The first landmark randomized, prospective trial published in this field, Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), (43) demonstrated, however, that high-dose atorvastatin does not slow the progression of this disease SALTIRE initiated atorvastatin in patients who had more advanced aortic stenosis as defined by the mean aortic valve area of 1.03 cm2, with heavy burden of calcification as measured by aortic valve calcium scores Newby et al recently acknowledged that the timing of therapy for aortic valve stenosis may play the key role in the future treatment of this disease The important issue may be treating this disease earlier in its process to slow the progression of bone formation in the aortic valve (44) The potential benefit of statin therapy, however, is controversial and widely debated, as recent randomized studies done in patients with moderate to severe degrees of aortic stenosis failed to consistently show substantial benefits

of this class of drugs Antonini et al provides evidence for a positive effect of statins in

reducing the progression of rheumatic AS and in a large series of patients with long-term follow-up, statins were effective in slowing the progression of aortic valve disease in aortic sclerosis and mild AS, but not in moderate AS These results suggest that statin therapy should be taken into consideration in the early stages of this common disease (23) The RAAVE (Rosuvastatin Affecting Aortic Valve Endothelium) study suggests that earlier treatment with statins is more efficacious in the prevention of progression of aortic valve stenosis than late treatment, similar to the effects of statins in the regression of vascular atherosclerosis (45) Importantly, results of the randomized trials will provide further evidence to define the treatment of this complex disease process, in which timing of therapy and characteristics of the valve lesion will need to be taken into account in the future treatment approaches In the RAAVE trial, the rate of progression of aortic stenosis in those with hypercholesterolemia treated with rosuvastatin is slower than in those with lower lipid levels who are not treated This is the first study to provide positive clinical evidence for the potential of targeted therapy in patients with asymptomatic aortic stenosis (45) Finally Parolari et al (46) performed a meta-analysis of studies was performed comparing statin therapy with placebo or no treatment on outcomes and on aortic stenosis progression echocardiographic parameters This meta-analysis identified 10 studies with a total of 3822 participants (2214 non-statin-treated and 1608 statin-treated) No significant differences were found in all-cause mortality, cardiovascular mortality or in the need for aortic valve surgery Lower-quality (retrospective or non-randomised) studies showed that, in statin-treated patients, the annual increase in peak aortic jet velocity and the annual decrease in aortic valve area were lower, but this was not confirmed by the analysis in high-quality (prospective or randomised) studies Statins did not significantly affect the progression over time of peak and mean aortic gradient Taken together, this evidences suggest that the progression of calcific aortic stenosis is a complex process; the multitude of the mechanisms involved in AS indicates that drug therapy should address the earliest stages of the disease,

as it is now evident that pharmacological treatment administered in more advanced stages

of the disease may be ineffective (47) At the end, all studies of statins have had the “wrong target” trying to treat patients with severely calcified valves In our opinion we should treat patients at earlier stages of the disease, since statins side-effects are considered marginal and moreover statins have been proven beneficial to delay atherosclerosis progression and CAD, than quite often accompany AS

Aortic valve replacement in patients without symptoms is controversial, infact asymptomatic patients with AS have outcomes similar to age-matched normal adults While the short-term prognosis in such patients is excellent without surgery, there is still a small but definite risk of sudden death Obviously there is also a small but definite risk of morbidity and mortality related to aortic valve replacement and to complications resulting from the presence of a prosthetic valve

4.4 Aortic valve replacement

When planning AVR, the chief issues related to surgical decision making involve the type of valve prosthesis to be inserted, the timing of surgery, and issues related to concomitant procedures The ideal prosthesis for AVR is characterized by excellent hemodynamics, minimal residual transvalvular pressure gradient, and laminar flow through the prosthesis

In addition, the valvular prosthesis should be durable, easy to implant, quiet, biocompatible, and resistant to thromboembolism The two major categories of valvular prostheses, which account for the vast majority of implanted aortic valves, include mechanical and bioprosthetic valves Regarding the decision between bioprosthetic and mechanical valves, the primary advantage of mechanical valves is their durability and

reliable performance Conversely, the primary disadvantage of mechanical valves relates to the need for lifelong warfarin anticoagulation and attendant lifestyle limitations and thromboembolic (TE) and bleeding risks When anticoagulation is managed appropriately, the risk of TE with mechanical valves is similar to that for bioprosthetic valves Bileaflet mechanical valves are the standard in current practice Conversely, the primary advantage

of bioprosthetic valves is that systemic anticoagulation with warfarin is not required As a result, patients receiving tissue valves have a lower rate of anticoagulation-related bleeding complications However, their limited durability (freedom from structural valve deterioration and need for reoperation) and suboptimal hemodynamics, due to a generally smaller effective orifice area size-for-size as compared to mechanical valves, have historically been the drawbacks of bioprosthetic valves As a result, use of bioprosthetic valves has generally been recommended for patients older than 65 years of age or with reduced life expectancy These tendencies are nowadays changing in light of improved tissue engineering, the increased lifespan of new generation tissue valves and the relative low risk of reoperation for isolate valve re-replacement Moreover, the increasing trend to use transcatheter aortic valve implantation (TAVI) and the possibility to replace a previously implanted biological prosthesis with the method of valve in valve, the implantatation of a trancatheter valve into the old and degenerated prothesis, without a new open heart operation, moves the needle of the balance toward greater use of biological prosthesis, even if the duration of TAVi in young patient is not still known

The most important problem in the use of mechanical prosthesis is anticoagulation for all the life Anticoagulation for the long-term treatment has been accomplished by vitamin K antagonists for the last half century Although effective under optimal conditions, the imminent risk of a recurrent adverse event of INR the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated But new anticoagulants which selectively block key factors in the coagulation cascade are being developed (48) Dabigatran is the first available oral direct thrombin inhibitor anticoagulant, it specifically and reversibly inhibits thrombin, the key enzyme in the coagulation cascade Its oral bioavailability is low, but shows reduced

interindividual variability Studies show a predictable pk/pd profile that allows for dose regimens The anticoagulant effect correlates adequately with the plasma concentrations of the drug, demonstrating effective anticoagulation combined with a low risk of bleeding Rivaroxaban will probably be the first available oral factor Xa (FXa) direct inhibitor anticoagulant drug It produces a reversible and predictable inhibition of FXa activity with potential to inhibit clot-bound FXa Its pharmacokinetic characteristics include rapid absorption, high oral availability, high plasma protein binding and a half-life of aprox

fixed-8 hours (49)

The development of new anticoagulant, safer , with less risk of bleeding, and which allow to the patient the possibility of a fixe assumption, without monitoring INR every week, could change the choice criteria between biological and mechanical prosthesis

4.5 Aortic balloon valvotomy

Percutaneous balloon aortic valvotomy (BAV) is a procedure in which 1 or more balloons are placed across a stenotic valve and inflated to decrease the severity of AS Although BAV

is useful in children with congenital AS, the calcified lesion of acquired AS in the adult does not respond well to BAV After a modest acute reduction in stenosis severity, restenosis recurs usually within 6 months Immediate hemodynamic results include a moderate reduction in the transvalvular pressure gradient, but the postvalvotomy valve area rarely exceeds 1.0 cm2 Despite the modest change in valve area, an early symptomatic improvement is usually seen However, serious acute complications occur with a frequency greater than 10% (50, 51)

5 The future

Prolonged life expectancy has resulted in an aging population and, consequently, in an increased number of patients with degenerative calcific aortic stenosis (52) AS has increased markedly in developed countries and AS, caused by valve calcification in the elderly, will continue to increase as the aging of society accelerates For symptomatic patients with severe aortic valve stenosis, open heart surgery for aortic valve replacement (AVR) with use

of cardioplegia under cardiopulmonary bypass remains the gold standard Although surgery is still the gold standard treatment, it is considered high risk in elderly patients because of high complication rates, which leads to substantial hesitation in submitting such patients to surgery The surgical approach is associated with substantial operative mortality rates in high-risk patients Consequently, almost one-third of patients with severe aortic stenosis are not offered surgery owing to a combination of reasons such as advanced age, impaired left ventricular function, re-do procedure, or multiple comorbidities (50) Moreover, as longevity within the general population is increasing, the proportion of aortic stenosis patients with contraindications for surgery is also expected to increase Decision-making is particularly complex in the elderly who represent a heterogeneous population, resulting in a wide range of operative risk, as well as life expectancy, according to individual cardiac and non-cardiac patient characteristics The two most striking characteristics of patients who were denied surgery were older age and LV dysfunction Age and LV dysfunction are associated with an increased operative risk and a poor late outcome after surgery, which may explain the reluctancy to operate on such patients Age is

a strong predictor of operative risk and poor late survival in cardiovascular surgery, in particular, in the case of AS Four percent of the elderly population has significant aortic

stenosis and the size of the population older than 65 years will grow 50% between 2000 and

2030 In very old patients with many comorbidities, the outcome of AVR is less favourable than in average poulation, and many of those patients may be inoperable or carry an unacceptably high perioperative risk Some patients with aortic valve disease defer surgery

in light of mild symptoms, whereas others are deemed too ill to undergo cardiac surgery The latter currently have been treated expectantly or by balloon aortic valvuloplasty (BAV), but this technique offers poor magnitude and durability of the physiologic improvement in aortic valve orifice area In most patients, balloon valvotomy reduces severe AS to moderately severe AS The gradient typically is reduced by 50% and averages approximately 35 mm Hg after the procedure Unfortunately, in 50% of patients, restenosis occurs within 6 months Overall, balloon valvotomy has not reduced the high mortality seen

in patients who do not undergo surgery for symptomatic AS Recent technological advances, however, now indicate that catheter techniques similar to those used for BAV can

be used for percutaneous aortic valve replacement, avoiding open cardiac access or the use

of cardiopulmonary bypass As with any medical procedure, the risk/benefit ratio of TAVI must be carefully considered The benefits provided by this novel procedure must be weighed eventually against what is considered today the “gold standard” that is surgical AVR Bearing in mind, however, the excellent track record of surgical AVR, it seems prudent to initially target those patients who are at high surgical risk due to severe comorbidities Thus, the patients currently enrolled in these studies are chosen based on a risk score, such as the EuroSCORE or STS score The other set of patients who may be considered at present are those with a deteriorated aortic bioprosthesis and deemed at high risk for surgical reoperation, and this “valve-in-valve” concept has already been reported With technological advancements, it is expected that the ease of implantation will improve and complications will decrease In order to consider lower risk and younger patients as candidates for this new technology, additional long-term durability data will be required before advocating this procedure as a possible substitute to surgical AVR Risk algorithms have been used to assess operative risk, anticipate outcomes, and provide for comparability

of patients among diverse centers and countries Unfortunately, these tools are inherently imprecise and frequently exclude comorbidities encountered in this population Therefore, the comparison of transcatheter procedural outcomes to anticipated results based upon predictive risk scoring remains somewhat subjective The presence of CAD has been clearly demonstrated to increase procedural risk with conventional aortic valve replacement However, its overall influence on outcomes of transcatheter therapy for aortic stenosis has not been clearly delineated This is especially true given the fact that TAVI is generally considered a stand-alone procedure, with variable degrees of concomitant coronary artery disease tolerated without intervention It has been shown that patients with CAD as indicated by previous CABG or PCI had significantly higher 30-day and overall mortality with transcatheter valve implantation

6 Risk stratification

The Euro Heart Survey has shown that, in current practice, there is general agreement between the decision to operate and the existing guidelines in asymptomatic patients However, in patients with severe symptoms, intervention is underused for reasons that are often unjustified This stresses the importance of the widespread use of careful risk stratification In the absence of evidence from randomized clinical trials, the decision to

intervene in a patient with VHD relies on an individual risk–benefit analysis, suggesting that improvement of prognosis compared with natural history outweighs the risk of intervention and its potential late consequences, in particular, prosthesis-related complications Factors predicting operative mortality have been identified from large series

of patients undergoing cardiac surgery or, more specifically, heart valve surgery They are related to heart disease, the patient’s age, comorbidity, and the type of surgery The easiest way to integrate the weight of the different predictable factors is to combine them in multivariate scores, enabling operative mortality to be estimated

6.1 Euroscore

It is a risk model which allows the calculation of the risk of death after a heart operation The model asks for 17 items of information about the patient, the state of the heart and the proposed operation, and uses logistic regression to calculate the risk of death First published in 1999, the model has been adopted worldwide, becoming the most widely used risk index for cardiac surgery, and its use is believed to have contributed substantially to the improvement in the results of heart surgery seen at the beginning of the millennium It is now aging and a new model (EuroSCORE 2010) is being prepared Briefly, comprehensive data were obtained for over 19,000 consecutive patients undergoing open heart surgery in

128 centers in eight European countries The database thus generated was subjected to multiple logistic regression analysis to determine which risk factors were associated with operative mortality Weights were allocated to each risk factor on the basis of the odds ratios and a risk model was constructed in which the percentage predicted mortality for a patient could be calculated by adding the weighted values of risk factors which are present The additive EuroSCORE model, by virtue of its nature, tends to underestimate risk in very high-risk patients Some very high-risk patients may be better assessed, for individual risk prediction, by using the full logistic EuroSCORE model EuroSCORE was initially designed

to be a user-friendly system, in the hope of encouraging as many units as possible to embark

on programs of risk-adjusted quality monitoring In this setting, although derived from a logistic regression methodology, only the simple additive version of the score was originally published This score could be easily calculated at the bedside and could therefore be used widely in Europe even in hospitals with little information technology Using the same risk factors, the logistic regression version of the score (the ‘logistic EuroSCORE’) can be calculated Many risk factors have been associated with cardiac surgical mortality and morbidity The EuroSCORE was derived from data obtained from patients operated on in

1995, and the details were first published in 1999 The system is now 10 years old, and is based on data that are even older Yet, since the introduction of EuroSCORE, there has been

a quantum improvement in cardiac surgical survival which mainly occurred during the first two to three years of the new millennium Evidence from countries with national databases has suggested that mortality in some of these countries has approximately halved, despite a gradual worsening of the risk profile of patients In the United Kingdom, for example, mortality has fallen to approximately 55% of logistic EuroSCORE prediction, giving a UK RAMR (risk adjusted mortality ratio obtained dividing the actual mortality by the predicted mortality) of around 0.55 In a consecutive series of patients with severe AS undergoing AVR, Kalavrouziotis and coworkers found that the logistic EuroSCORE was not an accurate risk assessment tool in all categories of risk but especially in high-risk patients Therefore, this predictive model should not be used to determine procedural risk in patients with

severe AS Furthermore, the utilization of the logistic EuroSCORE in the assessment of operability in patients with severe AS may not be appropriate

6.2 STS (Society of Thoracic Surgeons) risk score

More than 20 years ago, the STS was one of the first specialty organizations to recognize the importance of developing a prospectively maintained clinical data registry The resulting STS National Adult Cardiac Surgery Database (STS NCD) has achieved widespread acceptance by the provider community as well as interested third parties, including health policy researchers, government regulators, accrediting agencies, and payers The Society of Thoracic Surgeons’ risk models predict the risk of operative mortality and morbidity after adult cardiac surgery on the basis of patient demographic and clinical variables The models are primarily used to adjust for case mix when comparing outcomes across institutions with different patient populations The STS currently has three risk models: CABG, Valve, and Valve + CABG The models apply to seven specific surgical procedure classifications:

CABG model

1 Isolated Coronary Artery Bypass (CABG Only)

Valve model

2 Isolated Aortic Valve Replacement (AV Replace)

3 Isolated Mitral Valve Replacement (MV Replace)

4 Isolated Mitral Valve Repair (MV Repair)

Valve + CABG model

5 Aortic Valve Replacement + CABG (AV Replace + CABG)

6 Mitral Valve Replacement + CABG (MV Replace + CABG)

7 Mitral Valve Repair + CABG (MV Repair + CABG)

New STS models, developed using STS data from 2002 to 2006, account for endpoints as for operative mortality, permanent stroke, renal failure, prolonged ventilation (> 24 hours), deep sternal wound infection, reoperation for any reason, a major morbidity or mortality composite endpoint, prolonged postoperative length of stay, and short postoperative length

of stay Recently, the STS risk algorithm was reported to be the most sensitive score in defining the risk of patients undergoing isolated AVR Predictive value of many of the currently available scoring systems is insufficient to allow a reliable risk assessment in patients undergoing isolated aortic valve replacement The overestimation is most prominent in high-risk patients Risk stratification using the STS score was accurate in predicting the risk of mortality in high-risk patients Nevertheless, even this most recently built score systematically overestimates procedural risk From the clinician’s standpoint there is a need for an objective risk assessment tool

6.3 Do we need new or better tailored risk models?

Risk stratification models for operative mortality have gained widespread acceptance in cardiac surgery These models, however, are not 100% accurate A number of factors can influence their performance Generally speaking, available risk models for cardiac surgery

can be divided into three categories: (1) general cardiac surgery models - that is, coronary artery bypass surgery, valve surgery or other related cardiac surgery; (2) general valve surgery models; and (3) specific aortic valve surgery risk models Risk models can serve

multiple purposes if used correctly Firstly, risk models can be used for benchmarking; they may allow for control of procedural complexity when analyzing hospital and surgeon performance Secondly, risk models can help educate patients and improve informed patient consent Risk models can also be incorporated into guidelines to help identify high risk patients who may benefit from additional work-up or alternative treatment strategies If risk models can accurately identify high risk patients with expected longer lengths of stay in hospital, they may be useful for administrative logistic and budget planning Differences in epidemiology of disease, risk profiles, surgical strategies, decision making, selection bias, and referral bias can all influence the applicability and performance of a model Regarding EuroScore performance in valve surgery Parolari suggested that EuroSCORE might not be the appropriate tool for risk prediction in isolated valve operations or those combined with other cardiac procedures The area under the curve (AUC) derived from the meta-analysis

he performed provided estimates of 0.72 to 0.74, which are in a range of a performance considered less than satisfactory for a risk stratification algorithm EuroSCORE discrimination is also substantially lower with respect to the performance of the Society of Thoracic Surgery (STS) algorithm, which is about 0.8 for isolated valve operations and about 0.75 for valves plus CABG The explanation for this is that the STS score is updated almost annually, and, for this reason, it may better follow the changes occurring in valve patient population with relative ease, whereas the EuroSCORE is now undergoing its first revision since its introduction The discriminatory power and precision in risk prediction of the EuroSCORE in valve surgery has recently become increasingly important for two reasons The first is that in the most centers, valve procedures—either isolated or combined - actually represent more than 50% of the total caseload; therefore, accurate risk estimation in this patient population—mainly elderly and very elderly people—has become much more important The second reason is strictly related to the recent evolution in technical options in aortic valve operations that has led to a steady increase in the adoption of transcathether aortic valve procedures in patients at the highest risk or in very elderly people

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Etiology and Pathophysiology

Aortic Stenosis: Geriatric Considerations

Petar Risteski, Andreas Zierer, Nestoras Papadopoulos,

Sven Martens, Anton Moritz and Mirko Doss

Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe University

Germany

1 Introduction

In developed countries, the most frequent heart valve disease is aortic stenosis (AS) (Lung et al., 2003) Approximately, 25% of the population aged over 65 years have aortic valve thickening and some 3% of people older than 75 years have severe AS (Lindroos et al., 1993; Stewart et al., 1997) Its prevalence further increases with age and since life expectancy continues to extend, it is expected that the population of elderly patients with AS will grow

in future

Aortic valve replacement (AVR) is the gold standard treatment of severe and symptomatic

AS The current American College of Cardiology and American Heart Association as well as the European Heart Association Guidelines do not restrict operative treatment in relation to the age of the patient (Bonow et al., 2006; Vahanian, 2007)

Most of the large studies now report of more than 20% of patients undergoing surgery for

AS being over the age of 80 years (Charlson et al., 2006) Still, in every day clinical practise, advanced age is considered one of the main reasons to decline surgery

In the Euro Heart Survey on valvular heart disease (Lung et al, 2003), despite presence of severe and symptomatic AS, aortic valve surgery was refused in as many as 33% of elderly patients (defined as age over 75 years) Advanced age and left ventricular dysfunction were the most striking characteristics of the patients being refused, while comorbidities played a less important role

The decision to operate an elderly with AS must be carefully considered, and made then when the benefits of the operation, as compared to conventional treatment, outweigh the risk of the intervention

2 Natural history of aortic stenosis and conventional treatment

Drs Ross and Braunwald were the first to show that aortic stenosis develops latent over many years, with a near-to-normal survival until the symptoms develop (Ross & Braunwald, 1968) Once the symptoms of angina, dyspnea or syncope develop, the survival declines abruptly Around 75% of symptomatic patients will expire within 3 years after the onset of symptoms, without valve replacement The worst prognosis had the patients with global heart failure associated with severe AS, with a median survival of less than one year Some other more contemporary studies looked at the survival of patients after being medically or surgically treated for AS Bouma and coworkers identified three predictive

factors for poor outcome of non-operated patients with aortic stenosis (Bouma et al., 1999) Advanced heart failure (New York Heart Association Class III or IV), associated mitral regurgitation as well as severe left ventricular systolic dysfunction identified patients as high-risk for mortality, with a three-year survival of only 20% Their study showed a 3-year survival rate of 80% in the group of patients treated operatively versus only 49% in the group of patients treated medically Still, 41% of these patients with severe symptomatic AVS were treated medically

A similar survival pattern was observed in the study by Varadarajan and coworkers (Varadarajan et al., 2006) In their hands, surgically treated patients showed improved 1-year, 2-year and 5-year survival rates of 87, 78 and 68%, respectively, as compared with 52,

40 and 22%, respectively, in those managed medically

With this issue in hand, Pierard and coworkers from Brussels, Belgium have looked at the determinants and their prognostic impact of operative refusal or denial in octogenarians with severe AS (Pierard et al., 2011) Advanced age, a lower transaortic pressure gradient, a larger aortic valve area and presence of diabetes were identified as independent predictors

of AVR refusal or denial, which occurred in 40% of all patients with severe and symptomatic

AS, and had a profound impact on long-term prognosis, leading in a twofold excess mortality of patients treated without surgery (Pierard et al, 2011)

Nowadays, there is no reason to put into question the decision to perform the operation on

an elderly patient with severe AS, since optimal medical treatment remains ineffective when

AS becomes symptomatic

3 Operative treatment of elderly with AVS

Advanced age at the time of the operation has a strong influence upon the perioperative mortality and morbidity Bridgewater and co-workers, on behalf of the European Association

of Cardio-Thoracic Surgery, reported recently that early mortality following isolated AV surgery averaged 1.2% for patients under the age of 56 years, and progresses to 3.7% for patients between 71-75 years, further to 4.1% for patients between 76-80 years of age, and finally to 6.1% for patients older than 80 years (Bridgewater et al, 2010) The same authors also conclude, based on a survey on 40111 operated patients in developed countries that patients older than 80 years stay, on the average, more than 3 days longer than those under 61

This, however, represents a significant improvement of early results in contemporary aortic valve surgery as compared to outcomes reported two or three decades ago In a paper published in Circulation in 1994, from the group from Rennes, France, Dr Logeais and coworkers report of higher early postoperative mortality risk, averaging 6.2% for patients age 60-70 years, and 11.2% for patients older than 70 years of age (Logeais et al, 1994) A better understanding of the role of the preoperative respiratory preparation, improved myocardial protection of otherwise severely hypertrophic myocardium, as well as normothermic cardiopulmonary bypass may be attributed to the improved early postoperative results in the recent studies as compared to those several decades ago Another approach to improve early and long-term survival of elderly patients undergoing

AV surgery is to have them undergo surgery in due time Surgery in octagenarians, as reported by Pipper and coworkers (Pipper, 2009) should not be postponed until chronic myocardial decompensation finally convinces patients, relatives and cardiologists that AV surgery is inevitable, as the preoperative chronic decompensation strongly increases operative mortality and morbidity and negatively impacts long-term survival

The surgical community worked over the last two decades vigorously to reduce the trauma

of the conventional aortic valve operation Minimally invasive approaches like partial upper sternotomy have replaced the conventional complete median sternotomy when performing AVR in many centres Aiming for smaller incision, without compromising the quality of the operation and the effectiveness of myocardial protection, improved early outcomes have been reached

We reported the safety and reliability of AVR via a partial upper sternotomy in 2003 (Dogan

et al, 2003) In a prospective randomised trial, we showed that minimally invasive AVR can

be performed with only slightly longer operative times, good cosmetic results and improved rib cage stability as well as significantly less blood loss Furthermore, limited surgical access affected negatively neither the patients' neurological outcome nor the efficacy of myocardial protection

More recently, the implantation technique for AVR has been also modified, without compromise in hemodynamic performance of the valve substitute, all in order to reduce implantation times, and therefore the myocardium ischemia as well as cardiopulmonary bypass times We recently reported on the initial clinical experiences with the sutureless, nitinol-stented 3f Enable (Medtronic Inc., Minnesota, USA) aortic valve prosthesis in 32 patients Implantation time could be significantly reduced down to 9±5 minutes (Martens et al., 2009) The first report of multicenter experience with this particular valve substitute and implantation technique in 140 patients was published in the European Journal of Cardiothoracic Surgery in 2011 (Martens et al., 2011) Reproducibility as well as feasibility and safety with the ATS 3f Enable Bioprosthesis were demonstrated Valve implantation resulted in excellent hemodynamics and significant clinical improvement Further comparative studies are underway to prove the clinical benefit using this less-time-consuming implantation technique versus the conventional one

In the last few years, intensive interest has been put toward the development and perfection

of a catheter-delivered valve substitutes for use in patients with aortic stenosis in whom surgical therapy has been rejected (Walther et al, 2007a) Two delivery routes have been used to deploy the valve substitute in such patients

The transapical route (TAP-AVI – transapical aortic valve implantation), is the one used by the surgeons By avoiding the sternotomy incision, the cardiopulmonary bypass, aortic crossclamping as well as the cardioplegic cardiac arrest during the procedure, one aims at reduction of perioperative risk in an otherwise high-risk population of patients The vast majority of patients targeted for this therapy are elderly with multiple severe comorbidities rendering them as high-risk or not suitable for conventional AVR The mean age of the patients being reported on in the initial multicenter experience was 81 years (Walther et al., 2007b)

We went further on and compared our experience with TAP-AVI versus minimally invasive AVR through partial upper sternotomy in matched population of elderly patients (Zierer et al., JTCVS 2008) Mean age in our collectives were 85 years for the TAP-AVI group and 82 years for the ministernotomy group

Patient age, preoperative comorbidities and perioperative risk, expressed as logistic EuroSCORE (38%±14% for the TAP-AVI group and 35%±9% for the ministernotomy group) were matched between the groups Although the TAP-AVI approach was associated with faster postoperative recovery, early and late morbidity and mortality were comparable with those of the surgery group, suggesting that patient age and comorbidities are independent predictors of adverse outcome after AVR, regardless of the surgical approach

4 Long-term survival of elderly patients after AVR: the issue of left

ventricular hypertrophy

The long-term survival after the surgery, although superior to the medical treatment, is still not satisfactory Reported survival rates in all age groups range between 50% and 66% (David et al, 2001; Hammermeister et al, 2000) and further decrease to 18% at 15 years in patients older than 75 years of age (Jamieson et al., 1994) Several studies have related these poor results after AV surgery with the incomplete regression of the left ventricular hypertrophy (Levy, 1991; Rossi et al, 2000)

Left ventricular hypertrophy (LVH), a known complication of aortic stenosis, has been strongly associated with increased risk of sudden death, congestive heart failure, and overall cardiovascular mortality Incomplete regression of the LVH in patients undergoing AVR has been linked to the obstructive nature of the valve sewing ring and stent, or to patient–prosthesis mismatch, which are being held responsible for persistently elevated transvalvular gradients

In the late 1980s, stentless valves were introduced with the goal of maximizing the effective orifice area for flow by eliminating the valvular stent and sewing ring, therefore facilitating faster and more complete regression of LVH Over the next decade, several groups have published their initial results; many of them indicating faster and more complete regression

of left ventricular mass after stentless as compared with the stented AVR (Jin et al., 1996, Thomson et al., 1998) However, these advantages have been obtained in the setting of nonrandomized trials Our team had therefore set forth to determine, if we could measure these early and mid-term postoperative improvements in older patients receiving a stentless versus a stented bioprosthetic aortic valve, in a prospective randomized setting (Risteski et al., 2009)

Between September 1999 and January 2001, 40 patients with severe symptomatic aortic stenosis, over the age of 75 years, were randomly assigned to receive either the stented Perimount (n=20) or the stentless Prima Plus (n=20) bioprosthesis

The aortic valve was approached through a hockey stick aortotomy After complete resection ofthe native aortic valve and debridement of the aortic annulus,accurate sizing was carried out using the respective Carpentier–Edwardssizers for the Prima Plus stentless and the Perimount stentedvalves

The Prima Plus stentless valves were implanted in the subcoronary position The commissures were positioned 120° apart, withthe muscular shelf corresponding to the right coronary sinus.Care was taken to suture the base of the valve subannularly,to ensure that the coaptation line of the leaflets was at theheight of the native annulus Single interrupted unpledgeted4-0 braided polyester sutures were used for the proximal end,and the rims of the valve commissures were sutured to the nativeaorta using 4-0 polypropylene running sutures For the Carpentier–Edwards Perimount stented valve implantation, interrupted mattressed pledgeted 2-0 braided polyester sutures were placed circumferentially from below the annulus The valves were implanted in the supra-annular position, with the valvular stent positioned so as not to interferewith the coronary ostia

Clinical outcomes, left ventricular mass regression, effective orifice area, ejection fraction and mean gradients were evaluated at discharge, six months, one year and five years after surgery

Left ventricular mass index (LVMI) was calculated using the formula postulated by Devereux and Reichek, as follows:

LVMI (g/m2) = (1.05 x [(EDD + PWTd + IVSTd)3 – EDD3] – 13.6) / BSA

where the EDD is the LV end-diastolic diameter (cm), the PWTd is the LV postero-lateral diastolic wall thickness (cm), the IVSTd is the interventricular septum diastolic thickness (cm), and the BSA is the body surface area of the patient (Devereux & Reichek, 1997)

At five years, there were 5/20 (25%) deaths in the stentless group and 6/20 (30%) deaths in the stented group (all non-valve-related) There was one case of endocarditis in each group, early postoperatively All patients displayed continuous clinical improvement after the operation; at fiveyears, all of the survivors were in New York Heart Associationclass I or II Mean transvalvular gradients (Fig 1a) have remained consistently low throughout the follow-up with neither clinical nor statisticalrelevance in the differences between the groups

at any of thegiven time points Also noted was the lack of significant differencein the follow-up values of the effective orifice areas (Fig 1b) of both prostheses, although a tendency toward increaseof the same in both groups was obvious early in follow-up (at

12 months with regards to 6 months) only to disappearat the 5-year follow-up examination

Fig 1 Hemodynamic results after AVR with Edwards Perimount Stented Valve vs Prima Plus stentless valve in elderly (a) Mean transvalvular gradients (b) Mean effective orifice area (c) Left ventricular ejection fraction (d) Left ventricular mass index

The left ventricular ejectionfraction (Fig 1c) did not change over the time of follow-up.At 6 and 12 months, as well as at 5 years it did notdiffer between the groups The left ventricular mass index (LVMI,Fig 1d) did display a continuous rate of decrease in the firstyears after the surgery; however, this tendency was lost afterthe first year as the mean LVMI at 5 years was almost thesame to that at 12 months Finally, the index failed toreach the normal range

in both groups At all time points, thedifference between the groups did not reach statistical significance

At five years, stentless valves were not superior to the stented valves, with regards to hemodynamic performance, regression of left ventricular mass and clinical outcome Survival of the patients was not related to the nature of the biologic valve

Overall, the complexity of stentless valveimplantation with its prolonged cross-clamping times might notbe justifiable under these circumstances, if as we found, thesame results can

be achieved with a standard stented bioprosthesis Our results are in concordance with some other prospective randomizedstudies that emerged in the meantime (Ali et al., 2007, Perez de Arenaza et al., 2005)

by the nature of the valvular substitute, failing to justify a rather more complex implantation

of stentless valve substitute in an elderly patient

6 References

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